The histogenesis of several compartments in the mammalian central nervous system (CNS) entails orchestrated series of neuronal migration. In particular, the cerebral cortex and cerebellum contain different classes of neurons organized in a laminated manner that is the product of coordinated neuronal migration. Genetic studies in humans and mice reveal the importance of several gene products that are necessary for the intact cytoarchitecture of the cortex and cerebellum. For instance, mice lacking Cdk5 display an inverted layering of the cortex and cerebellar hypoplasia indicating that Cdk5 is indispensable for neurodevelopment. Cdk5 is a small serine/threonine kinase that requires association with a regulatory subunit for kinase activation. Two neuronal specific activators of Cdk5 have been isolated, specifically p35 and p39. This proposal will test the hypothesis that p35 and p39 are the essential activators of Cdk5 during neurodevelopment. Thus, a mouse strain with targeted deletion of both p35 and p39 loci will be created These animals will also be utilized to delineate the function of p35 versus p39 in neurodevelopment. Recently, a role of Cdk5 in neurodegeneration is reported. In AD brains, p35 is proteolytically cleaved to generated a truncated 25 kDA fragment (p25). The p25/Cdk5 kinase can induce tau hyperphosphorylation, cytoskeleton collapse and neuronal death. We will test whether p35 to p25 conversion is downstream from neurotoxic processes pertinent to neurodegenerative disease and identify the protease that is responsible for p35 cleavage in vivo. Furthermore, we will determine if p35 to p25 conversion is an important event for neurodegeneration. The proposed experiments will shed light on the regulation of Cdk5 in neurodevelopment and neurodegeneration.